Bipolar disorder (BD) is a highly impairing illness; when it occurs in children and adolescents, it tends to run a particularly severe course. Children with BD typically require extensive treatment with medication and, often, hospitalization. They have high rates of suicide attempts and have great difficulty navigating normal developmental milestones. Pediatric BD takes a very significant toll on children afflicted with the disease and their families.[unreadable] This study is designed to elucidate the brain mechanisms that mediate bipolar disorder (BD) in children and adolescents, and that confer risk of the illness in youth who have a parent or sibling with BD. We are testing the hypotheses that both youth with BD and those at risk for the illness by virtue of having a parent or sibling with BD will have deficits in processing of emotional stimuli, such as reward and punishment, or faces displaying emotion. These hypotheses are operationalized as follows: 1) children with bipolar disorder, or at familial risk for the illness, will have deficits labeling face emotion; 2) children with bipolar disorder, or at familial risk for the disorder, have difficulty adapting their behavior in response to changes in emotional stimuli in their environment; 3) these deficits will be mediated by dysfunction in ventral prefrontal-amygdala-striatal circuitry. Since the beginning of the project we have enrolled approximately 500 subjects, including youth with BD (approximately 100), youth at risk for BD (approximately 60), control subjects, and adults with BD. This year, approximately 75 new subjects were enrolled.[unreadable] Previous work on this project had identified deficits in face emotion identification in youth with BD, as well as deficits in response flexibility. Work this year extended these findings to youth at risk. Specifically, we demonstrated that youth at risk for BD have deficits in face emotion identification comparable to those seen in youth with the illness. We are currently analyzing data to test whether adults with BD have similar dysfunction. In addition, this year we performed fMRI neuroimaging studies to identify how brain mechanisms mediating this deficit differentiate youth with BD from those with severe irritability (see MH002786-07) and from those with attention deficit hyperactivity disorder (ADHD). When viewing faces and rating their emotional response to them, and to the emotion on the face, we found differences between irritable youth and those with BD in amygdala activation. We are currently performing fMRI studies with youth at risk for BD, and with adults with BD, to determine whether this amygdala dysfunction is present in children at risk, and whether it is unique to children with the disorder or present across the developmental spectrum.[unreadable] With regard to response flexibility, this year we obtained new findings both in youth at risk for BD and in youth with the illness. Although we have not, at this point, identified response flexibility deficits per se in youth at risk for BD, we have identified that they, like youth with the illness, have abnormally high variability in response time. This indicates difficulty sustaining attention to a task and, while it has been identified in other illness, such as ADHD, in our at risk population this deficit was independent of ADHD symptoms. More refined behavioral testing is now being conducted to determine the precise nature of this deficit. In youth with BD, we are using the new imaging modality magnetoencephalography (MEG) to identify deficits in response flexibility, especially those that occur in response to frustration. We have found that, in youth with BD, limbic, parietal, and prefrontal brain regions are particularly responsive to negative feedback, while in control subjects there is increased responsiveness to positive feedback. Planned studies will now compare these findings to youth with severe irritability, using both fMRI and MEG techniques.